Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 3 of 25 5.3.3 Processed Food and Feed (860.1520) ................................ ................................ ..... 18 5.3.4 Meat, Milk, Poultry and Eggs (860.1480) ................................ .............................. 19 5.3.5 Dietary Burden ................................ ................................ ................................ ........ 19 5.3.6 Estimated Secondary Residues in Livestock ................................ .......................... 19 5.3.7 Food Handling (860.1460) ................................ ................................ ...................... 19 5. 3.8 Water, Fish, and Irrigated Crops (860.1400) ................................ .......................... 19 5.4 Food Residue Profile ................................ ................................ ................................ ...... 19 6.0 Tolerance Derivation ................................ ................................ ................................ ......... 19 Appendix A. International Residue Limits Table. ................................ ................................ ....... 21 Appendix B. OECD MRL Calculation Procedure Inputs/Outputs. ................................ ............. 22 Appendix C. Proposed Metabolic Pathway for Fenbucon azole in Crops. ................................ ... 23 Appendix D. Fenbuconazole and Its Metabolites in Plants and Animals. ................................ ... 24Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 4 of 25 1.0 Executive Summary Fenbuconazole [ α - [2 - (4 - chlorophenyl)ethyl] - α - ph enyl - 1 H - 1,2,4 - triazole - 1 - propanenitrile] is a broad spectrum, triazole - type fungicide that acts by inhibiting sterol biosynthesis in fungi. It is currently registered for use on the following food/feed crops: almonds, apples, bananas, bushberries ( s ubgroup 13 - B), citrus fruits ( g roup 10) , cranberries, pecans, peanuts, peppers, stone fruits ( g roup 12) , sugar beets , and wheat. Permanent tolerances are established for th e combined residues of fenbuconazole and its lactone metabolites, RH - 9129 and RH - 9130 [trans or cis - 5 - (4 - chlorophenyl)dihydro - 3 - phenyl - 3 - (1 H - 1,2,4 - triazol - 1 - ylmethyl) - 2(3 H ) - furanone], expressed as parent in/on plant commodities at levels ranging from 0.05 ppm in/on almonds and pecans to 40 ppm in citrus oil [40 CFR §180.553(a)]. Permanent tolerances have also been established at 0.05 ppm for the combined residues in meat byproducts of cattle, goats, horses, and sheep. In this petition, a tolerance increase from 0.4 ppm to 1.0 ppm is being requested for the use of fenbuconazole on pepper s . The tolerance was established initially based on field trial data submitted for the Indar Water Soluble Packets ( WSP ) formulation. The registrant then submitted a bridging study to translate residue data from Indar 75WSP to the proposed new product Enable 2F , a suspension concentrate ( SC ) formulation of fenbuconazole . The bridging study was conducted using bell peppers and consisted of side - by - side trials in six different locations, in which both formulations were applied in accordance with the maximum labeled use rate. The bridging data indicated that residues values could be higher than the current 0.4 ppm tolerance, for both the existing WSP use and the proposed new SC formulation use on peppers . HED ‘s previous review of the formulation bridging study indicated that a 1.0 ppm tolerance i s appropriate ( D390352, S. Oo nnithan, 8 Sept 2011 ) . The 75% WP formulation of fenbuconazole (INDAR ® 75WSP; EPA Reg, No . 62719 - 421) is currently registered for use on peppers . The proposed use is for up to four broadcast foliar applications to peppers at up to 0. 188 lb ai/A/applicati on with a minimum retreatment interval (RTI) of 10 days, for a maximum seasonal use rate of 0.75 lb ai/A. Applications may be made using either ground or aerial equipment. The minimum preharvest interval (PHI) is 7 days for peppers. In conjunction with this use, Dow AgroSciences is proposing the following permanent tolerance for the combined residues of fenbuconazole and its lactone metabolites, RH - 9129 and RH - 9130, expressed as fenbuconazole :

Pepper ................................ ................................ .................. 1.0 ppm The qualitative nature of fenbuconazole residues in plants is adequately understood based upon adequate peanut, peach, sugar beet and wheat metabolism studies. The residues of concern in/on p eppers are the parent fenbuconazole (RH - 7592) and its lactone metabolites, RH - 9129 and RH 9130. The qua litative nature of the residue in livestock is adequately understood. Based on adequate ruminant metabolism data, the residues of concern in animal matrices are fenbuconazole and its lactone metabolites, RH - 9129 and RH - 9130. Although the poultry metaboli sm studies were deemed inadequate, additional poultry metabolism data are not required for this petition as theFenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 5 of 25 expected dietary exposure of poultry is low (0.09 ppm) and the available metabolism data and poultry feeding study indicate that tolerances will not be required for poultry commodities. An adequate Gas Chromatography

– Nitrogen Phosphorous Detector (GC - NPD) Method (Report No. TR 34 - 99 - 41 R ) has been proposed for enforcing tolerances for residues of fenbuconazole and its lactone metabolites, RH - 912 9 and RH - 9130, in p eppers . The limits of quantitation (LOQ) and limit of detection (LOD) of the method for each of the analytes were set at 0.01 ppm and 0.003 ppm, respectively for each analyte. Adequate confined rotational crop studies are available and indicate that the metabolite profile in rotational crops is similar to the metabolite profile in primary crops. For rotational crops other than the primary crop, the submitted rotational crop study support s a 210 - day plant - back interval (PBI) followin g fenbuconazole applications totaling 1.0 lb ai/A, and a 35 - day PBI following applications totaling up to 0.188 lb ai/A. Limited field rotational crop trials and rotational crop tolerances are not required. 2.0 R egulatory R ecommendations HED has examine d the residue chemistry database for fenbuconazole . T here are no residue chemistry issues that would preclude increasing the tolerance for fenbuconazole on peppers . T he recommended tolerance is listed in Table 2.2.2. 2.1 Data Deficiencies/Data Needs NA 2.2 Tolerance Considerations 2.2.1 Enforcement Analytical Method The available GC/NPD method , TR 34 - 90 - 47R , is adequate for enforcing tolerances and collecting data on fenbuconazole residues in/on peppers. 2.2.2 Recommended Tolerances The tolerance expression should be revised to read : “ Tolerances are established for residues of the fungicide fenbuconazole, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels speci fied below is to be determined by measuring only the sum of fenbuconazole, alpha

– [2

– (4

– chlorophenyl)

– ethyl]

– alpha

– phenyl

– 3

– (1H

– 1,2,4

– triazole)

– 1

–

propanenitrile, and its metabolites RH

– 9129, cis

– 5

– (4

– chlorophenyl)

– dihydro

– 3

–

phenyl

– 3

– (1H

– 1,2,4

– triazole

– 1

– ylmethyl)

– 2

– 3 H

– furanone, and RH

– 9130, trans

– 5

– (4

– chlorophenyl) - dihydro

– 3

– phenyl

– 3

– (1H

– 1,2,4

– triazole

– 1

– ylmethyl)

– 2

– 3 H

– furanone , calculated as the stoichiometric equivalent of fenbuconazole, in or on the following agricultural commodities.”Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 6 of 25 Table 2.2.2 . Tolerance Summary for Fenbuconazole. Commodity Established/Proposed Tolerance (ppm) HED - Recommended Tolerance (ppm) Comments

( correct commodity definition ) Pepper 0.4 ppm 1.0 ppm Commodity definition: Pepper 2.2.3 Revisions to Petitioned - For Tolerances None. 2.2.4 International Harmonization As summarized in Appendix A, m aximum residue limits (MRLs) for residues of fenbuconazole have been established by Codex , Ca nada, and Mexico. The residue definition for both Codex and Mexico is fenbuconazole, and the Canadian residue definition is the combined residues of fenbuconazole and its metabolites, RH - 9129 and RH - 9130, each expressed as parent ( i.e. , the same as the U.S. tolerance definition) . The Codex MRL for pepper is 0.6 ppm and was most likely established before the Enable 2F formulation was proposed for use on peppers, and includes only residues of the parent compound. This new formulation has higher residues values ranging up to 0.7 ppm, and does include the two lactone metabolite s. Harmonization with the 0.6 ppm tolerance is not feasible given the proposed new use pattern . T here is no extant Canadian or Mexican MRL , for f enbuconazole on pepp ers, and thus there are no harmonization issues in North America . 2.3 Label Recommendati ons The following rotational crop restrictions should appear on the final label: the minimum plant back interval is 35 days when the last application of the product is <0.188 lb ai/A, and 210 days when the last application of the product is 0. 188 - 1 .0 lb a i/A. 3.0 Introduction Fenbuconazole is a broad spectrum, triazole - type fungicide used to control various fungal diseases. It acts by inhibiting sterol biosynthesis in fungi (MOA Group 3). Fenbuconazole is formulated as a 2 - lb ai /gal SC and a 75% WP ; both currently registered to Dow AgroSciences, LLC, for use on almonds, apples, bananas, bush berries , citrus fruits, cranberries, pecans, peanuts, stone fruits , sugar beets, and wheat.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 7 of 25 3.1 Chemical Identity Table 3.1. Fenbuconazole Nomenclature. Compound

Common name Fenbuconazole Company experimental name RH - 7592 IUPAC name ( RS ) - 4 - (4 - chlorophenyl) - 2 - phenyl - 2 - (1 H - 1,2,4 - triazol - 1 - ylmethyl)butyronitrile CAS name α - [2 - (4 - chlorophenyl)ethyl] - α - phenyl - 1 H - 1,2,4 - triazole - 1 - propanenitrile CAS # 114369 - 43 - 6 End - use product/EP 75% WP (Indar ® 75 WSP Fungicide, EPA Reg. No. 62719 - 421) Metabolites

cis and trans isomers Common name cis and trans lactone metabolites; Lactones A and B Company experimental names RH - 9129 and RH - 9130 IUPAC names (3R,5R) or (3S,5R) - 5 - (4 - chlorophenyl) - 3 - phenyl - 3 - (1H - 1,2,4 - triazol - 1 - ylmethyl)dihydrofuran - 2(3H) - one CAS names trans - or cis - 5 - (4 - chlorophenyl)dihydro - 3 - phenyl - 3 - (1 H - 1,2,4 - triazol - 1 - ylmethyl) - 2(3 H ) - furanone CAS # cis isomer, 146887 - 38 - 9; trans isomer, 146887 - 37 - 8 3.2 Physical/Chemical Characteristics Table 3. 2. Physicochemical Properties of the Technical Grade Fenbuconazole Parameter Value Reference Melting point 126.5

– 127.0°C DP# D310959, S. Oonnithan, 7/25/2006 pH not available Bulk Density 0.50 g/mL Water solubility at 22°C 3.8 mg/LFenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 8 of 25 Table 3. 2. Physicochemical Properties of the Technical Grade Fenbuconazole Parameter Value Reference Solvent solubility (g/L) at 25°C A cetonitrile : 231 C yclohexanone : 445 ethyl alcohol : 39 1 - octanol : 13 aromatic 200 : 77

ethyl acetate: 159 heptane : 1.0 Vapor pressure at 25°C (PAI) 3 . 7 ×10 - 8 mm Hg (4.9 × 10 - 6 Pa) Dissociation constant (pK a ) (PAI) Not expected to dissociate in water Octanol/water partition coefficient Log(K OW ) 302 ± 0.08 UV/visible absorption spectrum λ max (nm) ε (L mol - 1 cm - 1 ) 196 53,000 262 750 268 740 275 480 3.3 Pesticide Use Pattern/ Directions for Use (860.1200) Dow AgroSciences is proposing the first use of Enable 2F TM (2.0 lbs ai/gallon , EPA Reg . No . 62719 - 41 6) on peppers. T he proposed use directions are summarized below in Table 3 .3 . Table 3.3. Summary of Directions for Use of Fenbuconazole . Applic. Timing, Type, and Equip. 1 Formulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations 2 Peppers (Including but not limited to: bell, chili, cooking, non - bell, pimento and sweet) Broadcast foliar applications to peppers when disease first appears Ground or aerial equipment 75% WP [62719 - 421] 0.188 3 NS 0.75 7 Apply in a minimum of 30 gal/A, using ground equipment. The minimum RTI is 10 - 14 days. Broadcast foliar applications to peppers when disease first appears Ground or aerial equipment 2.0 lbs ai/gal . SC [62719 - 416] 0.188 3 NS 0.75 7 Apply in a minimum of 30 gal/A, using ground equipment. The minimum RTI is 10 - 14 days. 1 Do not apply through any type of irrigation system. Although application using aerial equipment is permitted, ground application is recommended. 2 Rotational crop restrictions: the minimum plant - back interval is 35 days when the last application of the product is <0.188 lb ai/A, and 210 days when the last application of the product is 0. 188 - 1 .0 lb ai/A. 3 The maximum use rate is based on the use of 4 oz product/acre/application. NS = not specified. Conclusions : The use directions are adequate to allow for evaluation of the residue data relative to the proposed use. The available field trial data and formulation bridging data on peppers are adequate and support the proposed use ( 4 oz product/A is equivalent to 0.188 lb ai/A ) . Although the single application rates used in the field trials were ~0.167 lb ai/A (0.9x rate), the residue data from these tests are adequate to support the 0.188 lb ai/A/application rate.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 9 of 25 4.0 Metabolite/Degradate Residue Profile 4.1 Nature of the Residue The qualitative nature of fenbuconazole residues in plants and livestock is adequately understood . Adequate studies are available depicting the metabolism of [ 14 C]fenbuconazole in peaches, peanuts, sugar beets, and wheat. The residues of concern in/on peppers are fenbuconazole, its lactone metabolites, RH - 9129 and RH - 9130 . In addition , the triazole metabolites 1,2,4 - triazole, triazole alanine, and triazole acetic acid are resi dues of concern for risk assessment . These metabolites are common to the triazole - derivative class of fungicides and are addressed in a risk assessment separate from that for fenbuconazole . There are no livestock feedstuffs associated with the use on pep pers; t herefore, data requirements for livestock metabolism are not relevant to this tolerance petition 4.1.1 Summary of Plant Metabolism (860.1300) MARC Decision Memo (N. Dodd and W. Wassell, 3/9/94) D200171, N. Dodd, 4/5/94 D241864, PP# 7F4887 - sugar beets Adequate studies are availab le depicting the metabolism of fenbuconazole in peaches, peanuts, wheat, and sugar beets. Results from peach, wheat and peanut studies were previously summarized for review by the HED Metabolism Committee (Memo, N. Dodd and W. Wassell, 12/10/93), and the sugar beet metabolism study is summarized under the petition for use on sugar beets (D241864, PP# 7F4887 , 30 Mar 2006 ). Based on the peach and wheat studies, the Metabolism Committee concluded that the residues of concer n for uses on stone fruit, wheat, pecans, bananas, apples and almonds are fenbuconazole and its lactone metabolites, RH - 9129 and RH - 9130. This conclusion was contingent upon the petitioner providing data showing that RH - 4911 is only a minor residue in the se crops. The petitioner subsequently fulfilled this requirement by providing data from the wheat and peach metabolism studies showing that conjugates of RH - 4911 accounted for <5% of the TRR in peaches and wheat straw (D200171, N. Dodd, 4/5/94). The Meta bolism Committee also noted that the iminolactone metabolite (RH - 6468) would be included de facto in the residues of concern as this compound is converted to the lactones by the analytical methodology. In the peanut metabolism study, vine and nutmeat sa mples were collected 28 days after the last of four foliar applications of either [phenyl 14 C] or [triazolyl 14 C] fenbuconazole (6.8% EC) at one - month intervals, at rates totaling ~2 lb ai/A. For both 14 C - labels, the major residues in vines were parent (4 5 - 54% TRR), RH - 9129 (4 - 5% TRR), RH - 6467 (8 - 10% TRR), and the glucose conjugates of 4911 (18 - 19% TRR). Triazole alanine (7% TRR) was also identified in the [triazolyl 14 C] - labeled vines. The major residues in nutmeats were triazole alanine (88% TRR) from the [triazolyl 14 C] - label and the glucose conjugate of 4911 (29% TRR) from the [phenyl 14 C] label. In nutmeats, 29.4% total radioactive residue (TRR) w as present as RH - 7905 and in peanut vines, 24.5% of TRR was found as the glucosyl and glucosyl - malonyl c onjugate s of RH 4911. Based on this data, for peanut commodities only, residues of RH - 7905 ( the glucosyl metabolite of RH - 4911, determined as RH - 4911 ) are also included in the risk assessment .Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 10 of 25 In addition to the above metabolism studies, an adequate sugar beet metabolism study was reviewed (D241864, 44343303.der) in conjunction with a petition for use on sugar beets. In this study, [phenyl 14 C] fenbuconazole was applied to sugar beets as three foliar applications at 39, 103, and 183 days after planting, at rates totaling 3 lb ai/A, and samples of tops and roots were collected 7 days after the final application. The major residue identified in both tops and roots was parent (83 - 91% TRR), along with minor amounts of the lactone metabolites (<3% TRR). Afte r reviewing the sugar beet data, HED has also determined that fenbuconazole and it lactone metabolites are the residues of concern for uses on sugar beets (D241864, PP# 7F4887 , 30 Mar 2006 ). Conclusions : Adequate studies are available depicting the metab olism of [ 14 C]fenbuconazole in peaches, peanuts, sugar beets, and wheat. The qualitative nature of fenbuconazole residues in plants is adequately understood. The residues of concern in/on peppers for tolerance setting are fenbuconazole and its lactone me tabolites, RH - 9129 and RH - 9130 . A separate risk assessment will be conducted for the triazole metabolites, 1,2,4 - triazole, triazole alanine, and triazole acetic acid. All t he metabolites are identified in Table 4.2.1 , with the full details on their chemi cal structure summarized in Appendix D . 4.1.2 Summary of Livestock Metabolism (860.1300) D182306, D182303, D181531, D181529, D181494, D195098, and D181498; W. Wassell; 1/11/94 D212471 and D212472, W. Wassell, 8/8/95 D223761 and D223758, W. Wassell, 4/23/9 6 There are no livestock feedstuffs associated with the established or proposed use s on peppers; t herefore, data requirements for livestock metabolism are not relevant to this tolerance petition T he available goat and poultry metabolism data are adequate and HED concluded that , f or ruminants, the residues of concern in animal matrices are fenbuconazole and its lactone metabolites, RH - 9129 and RH - 9130. Although the poultry metabolism studies were deemed inadequate, a new poultry metabolism is not required at this time, as the available data are sufficient to conclude that tolerances will not be required for eggs and poultry tissues. Based on the current and proposed uses of fenbuconazole, the maximum dietary burden for poultry is expected to be low (0.063 ppm). The poultry metabolism studies were conducted at highly exaggerated rates (1,600x), and correcting residues levels in eggs and tissues from the metabolism studies to a 10x level indicates that individual residues in eggs and tissues will be <0.01 p pm. In addition, the results from the available poultry feeding study support this conclusion. If future uses of fenbuconazole result in a substantial increase in the dietary burden for poultry, then a new poultry metabolism study will be required. Metabolism and distribution were investigated in lactating goats. In goats dosed at levels equivalent to 1, 10 and 100 ppm in the feed, less than 0.5% of the TRR remained in the milk and less than 1.6% in the tissues. Two major metabolites were identified in t he milk as 1,2,4 - triazole (0.24 mg/kg fenbuconazole equivalents at the highest dose) and triazolyl alanine (TA, 0.15 mg/kg at the highest dose), with very low levels of the parent compound. At the highest dose, the levels of the TRR in the liver, kidney, m uscle and fat were 12.4, 0.97, 0.22 and 0.11 mg/kgFenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 11 of 25 respectively. In the liver five major components were identified: the parent compound (0.95 mg/kg), 4 - (4 - chlorophenyl) - 2 - hydroxymethyl - 2 - (phenyl)butanenitrile (RH - 7968, 0.95 mg/kg), the glucuronide of the 4 - hydroxy derivative (1.23 mg/kg), the triazole (1.79 mg/kg) and TA (4.95 mg/kg). A further phenol metabolite was present in the kidney. Conclusion s : The available goat and poultry metabolism data are adequate for purposes of this petition and HED concl uded that, for ruminants, the residues of concern in animal matrices are fenbuconazole and its lactone metabolites, RH - 9129 and RH - 9130. The poultry metabolism studies were conducted at highly exaggerated rates (1,600x), and correcting residues levels in eggs and tissues from the metabolism studies to a 10x level indicates that individual residues in eggs and tissues will be <0.01 ppm . There are no livestock feedstuffs associated with the established or proposed use s on peppers; t herefore, data requiremen ts for livestock metabolism are not relevant to this tolerance petition 4.1.3 Summary of Confined Rotational Crops (860.l850) D259204, S. Oonnithan, 7/25/06 An adequate confined rotational crop study is available indicating that the metabolite profile for fenbuconazole i n rotational crops is similar to the metabolism in primary crops. Limited rotational crop field trials and rotational crop tolerances are not required provided that the labels specify a minimum PBI of 35 days following the last applicat ion to peppers of ≤0.188 lb ai/A , and a minimum PBI of 210 days following a last application of 0.188 - 1.0 lb ai/A. 4.1.4 Summary of Rat Metabolism In a rat general metabolism study (MRID 42900801), the absorption, distribution, metabolism and excretion of RH - 7592 (fenbuconazole technical ) were evaluated in Crl:CD BR rats (5/sex/group) dosed by a single gavage dose at 1 or 100 mg/kg in 5% aqueous methylcellulose vehicle (5 mL/kg) . Figure 1 summarizes the proposed metabolic pathways of fenbucona zole in rats. Radiolabeled RH - 7592 was rapidly absorbed, distributed and excreted following oral administration in rats. Total 3 - or 4 - day recoveries of the radioactivity were high for all groups (90.40 - 104.49% of the administered dose, or AD). Biliar y excretion data indicated that systemic absorption of RH - 7592 was high for all dosing groups. The feces were the major route of excretion (78.74 - 94.43% AD) after 4 days post dosing , while recovery in the urine was low (<1% AD). Tissue bioaccumulation of RH - 7592 appeared to be minimal since <1% AD was recovered in tissues 4 days after oral administration for all dose groups. Except for the gastrointestinal tract, the highest levels were found in the liver (0.08 to 4.217 ppm). No sex - or dose - related di fferences in absorption, distribution or elimination were found. Metabolism of RH - 7592 was extensive as shown by the numerous metabolites characterized and isolated in the feces, bile and urine. Metabolic pathways included glucuronide and sulfate conjuga tion, hydroxylation and oxidation . Furthermore, a dose - related difference in metabolism was evident. The higher amount of unmetabolized parent compound in the feces of the high dose group compared to the low - and repeated - dose groups suggest that saturat ion of the metabolic pathw ay may occur at the high dose.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 12 of 25 4. 1.5 Summary of Environmental Degradation Fenbuconazole is considered to be moderately persistent to persistent in the environment and slightly mobile to mobile in soils. Because of its adsor ption to soil, the potential for fenbuconazole to leach to ground water appears to be slight. However, the potential to contaminate groundwater may be greater at vulnerable sites, i.e. , where soils have low organic matter and where groundwater is relative ly close to the surface. The long half - lives of fenbuconazole in aerobic soil and terrestrial field dissipation studies indicate that when fenbuconazole is applied over multiple growing seasons, soil residue accumulation may result. These residues may be available for rotational crop uptake or may be transported with sedimentsFenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 13 of 25 during runoff events. For purposes of human health risk assessment, the residue of concern in water is fenbuconazole . 4.1.6 Summary of Metabolites and Degradates As summarized in Appendix C, t he metabolic pathway in plants consists of three major routes. The first route is via oxidation of the carbon next to the chlorinated phenyl ring, forming the benzilic alcohol intermediate , which fur ther reacts to form the lactone metabolite s RH9129 and RH 9130 (which are diastereomers). Oxidation or nucleophilic substitution of th e carbon adjacent to th e triazole ring leads to the formation of the free triazole, which is transformed into triazole - alanine and the triazole acetic acid. Anoth er route involves the hydrolation of fenbuconazole, which leads to the formation of various conjugates, including glucuronide and malonyl - glucoside conjugates. Based on adequate ruminant metabolism data, the residues of concern in animal matrices are fenbuconazole and its lactone metabolites, RH - 9129 and RH - 9130. Residues of RH - 7968 were a minor component of the total radioactive residues (≤7.2% TRR) in goat liver, muscle and fat in the supplemental goat metabolism study, this metabolite is not includ ed in the tolerance expression for animal commodities. Although the poultry metabolism studies were deemed inadequate, additional poultry metabolism data are not required for this petition as the expected dietary exposure of poultry is low (0.09 ppm) and the available metabolism data and poultry feeding study indicate that tolerances will not be required for poultry commodities. 4. 2 Comparison of Metabolic Pathways S tudies are available depicting the metabolism of [14C]fenbuconazole in rats, primary crop s (peaches, peanuts, wheat, sugar beets), rotational crops (collards, turnips, wheat), and livestock (lactating goats, laying hens). Major residues consistently noted in these studies include parent fenbuconazole and the lactone metabolites RH - 9129, RH - 91 30, and for peanuts only, the metabolite RH - 6467. The common triazole metabolites 1,2,4 - triazole, triazolylalanine, and triazolylacetic acid were observed in all of the metabolism studies, with the degree of metabolite formation highly dependent on the sp ecies being studied. In rats, fenbuconazole is rapidly absorbed and excreted within 96 hours following a single low or high dose or following repeated low doses. Very l ow bioaccumulation of both the parent compound and metabolites was indicated by low levels in the tissues. Elimination occurred primarily by biliary excretion since the majority of the administered dose was recovered in the bile three days after exposure or in the feces four days after exposure. There were no sex - or dose - related diff erences in absorption, distribution, or elimination; these processes were also similar regardless of whether single or multiple exposure regimens were used. Extensive metabolism of fenbuconazole occurred, with sex - and dose - related differences. Very low (2 - 5%) parent compound was recovered in the feces following single or repeated low doses, but a higher percentage (21 - 37%) was found following a single high dose , indicating saturation of the metabolic pathway . More sulfate metabolites were found in femal e excreta compared to males, and more ketoacid metabolites were found in male urine compared to females.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 14 of 25 Based on the peach and wheat studies, the Metabolism Committee (N. Dodd and W. Wassell, 3/9/94) concluded that the residues of concern for uses on stone fruit, wheat, pecans, bananas, apples and almonds are fenbuconazole and its lactone metabolites, RH - 912 9 and RH - 9130. This conclusion was contingent upon the petitioner providing data showing that RH - 4911 is only a minor residue in these crops. The petitioner subsequently fulfilled this requirement by providing data from the wheat and peach metabolism stu dies showing that conjugates of RH - 4911 accounted for <5% of the TRR in peaches and wheat straw (D200171, N. Dodd, 4/5/94). The Metabolism Committee also noted that the iminolactone metabolite (RH - 6468) would be included de facto in the residues of concer n as this compound is converted to the lactones by the analytical methodology. After reviewing the sugar beet data, HED has also determined that fenbuconazole and it lactone metabolites are the residues of concern for uses on sugar beets (D241864, PP# 7F4 887). Metabolite studies with peanuts show that RH - 7905 and RH - 4911 are significant residues of concern in this crop only (see Section 4.3) . 4.3 Residues of Concern Summary and Rationale MARC Decision Memo (N. Dodd / W. Wassell, 3/9/94) D182303, W. Wassell , 1/11/94 D200171, N. Dodd, 4/5/94 D212471, W. Wassell, 8/8/95 D223758, W. Wassell, 4/23/96 D403618 , T. Morton , 8/1/2012 . HED has determined that the residues of concern for risk assessment are fenbuconazole and the following metabolites: RH - 9129, RH - 9 130, RH - 4911(peanut only), and RH - 7905 (peanut only). RH - 9129 and RH - 9130 are cis/trans isomers of the lactone metabolite of fenbuconazole and may account for approximately one third of the total fenbuconazole residues. RH - 9129 and RH - 9130 are residues o f concern for both risk - assessment and tolerance - enforcement purposes. RH - 7905 is a minor metabolite except in peanut. In animals, the glucoside conjugate (RH - 7905) will be cleaved to yield RH - 4911. Although RH - 4911, being a hydroxy - derivative of fenbuc onazole, is likely to be less toxic than the parent, we have no specific toxicological information for this compound. Because it shares structural features with the parent, HED is assuming that it has the same toxicity as fenbuconazole. Therefore, RH - 790 5 and RH - 4911 are being included as residues of concern for risk assessment (peanuts only). The current analytical enforcement method has been validated for the analysis of fenbuconazole as well as RH - 9129 and RH - 9130. In addition, the Metabolism Committee noted that the iminolactone metabolite (RH - 6468) would also be included de facto in the residues of concern, as the petitioner has indicated that this compound is converted to the lactones by the analytical method. In addition, a lthough the poultry metabolism studies were deemed inadequate, additional poultry metabolism data are not required for this petition as the expected dietary exposure of poultry is low (0.09 ppm) and the available metabolism data and poultry fee ding study indicate that tolerances will not be required for poultry commodities.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 15 of 25 Table 4. 3. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression * Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Fenbuconazole + RH - 9129 + RH 9130 + RH - 7905 (peanut only) + RH - 4911 (peanut only) Fenbuconazole + RH - 9129 + RH - 9130, expressed as fenbuconazole Rotational Crop Not Applicable Not Applicable Livestock Ruminant Fenbuconazole + RH - 9129 + RH 9130 Fenbuconazole + RH - 9129 + RH - 9130, expressed as fenbuconazole Poultry Not Applicable Not Applicable Drinking Water Fenbuconazole Not Applicable * The common triazole metabolites 1,2,4 - triazole, triazolylalanine, and triazolylacetic acid have been identified as residues of concern for risk assessment. Separate assessments addressing these compounds have been conducted ( see. T. Morton. D403618. 8/1/2012 ). 5.0 Residue Profile 5.1 Residue Analytical Methods (860.1340) 5.1 .1 Data Collection Methods See Tolerance Enforcement Method (Section 5.1.3) 5.1.2 Multi - Residue Methods (860.1360) Data evaluating the recovery of fenbuconazole and the metabolites RH - 9129 and RH - 9130 through FDA Multi residue Method Testing Protocols were submitted and forwarded to FDA for further review (Letter to L. Sawyer from N. Dodd, 1/27/93). The FDA PESTDATA database, dated 11/01 (PAM Vol. I, Appendix I), indicates that fenbuconazole is completely recovered using Multi residue Methods Section 302 (Protocol D), but is not recovered by Methods 303 and 304 (Protocols E and F). The recovery of the lactone metabol ites (RH - 1929 and RH - 9130) through Method 302 was variable or partial (50 - 80%). None of these metabolites were recovered through Methods 303 or 304. 5.1 .3 Tolerance Enforcement Method 44869103.der A GC/NPD tolerance enforcement method , 34 - 90 - 47R , is ava ilable for determining residues of fenbuconazole, RH - 9129 , and RH - 91 30 in/on stone fruits. For this method, residues are extracted with methanol , filtered through Celite, diluted with aqueous 9.1% NaCl, and partitioned into methylene chloride. Residues a re then concentrated, redissolved in toluene:acetone (100:10 , v:v ) , and cleaned up using a silica gel column eluted with toluene:acetone (100:30 , v:v ). Residues in the resulting eluat e are concentrated to dryness, redissolved in toluene:acetone (100:5 , v/v ) , and eluted through a Florisil column with toluene:acetone (100:30 , v:v ). Residues are again concentrated to dryness, redissolved inFenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 16 of 25 toluene:methanol (100:3 , v:v ), and analyzed by GC/NPD using external standards. The reported LOQ is 0.01 ppm each fo r fenbuconazole, RH - 9129, and RH - 9130. Residues in/on peppers were determined using a slightly modified version of the above method. The modifications were made to improve the performance of the method. The GC/NPD method was adequately validated in conju nction with the analysis of field trial samples using control samples fortified with each analyte at 0.01 - 1.0 ppm. The validated LOQ for each analyte is 0.01 ppm in/on peppers, for a combined LOQ of 0.03 ppm. Conclusions : The available GC/NPD method , TR 34 - 90 - 47R , is adequate for enforcing tolerances and collecting data on fenbuconazole residues in/on peppers . Note: The GC/NPD method (TR 34 - 94 - 142) is adequate for collecting data on residues of fenbuconazole, RH - 9129 and RH - 9130 in animal commodities. 5.2 Storage Stability (860.1380) D249012, W. Wassell, 11/19/98 D223761 , W. Wassell. 4/23/96 D239002, G. Otakie, 3/30/06 Adequate s torage stability data are available indicating that fenbuconazole and its lactone metabolites (RH - 9129 and RH - 9130) are stable in frozen storage for up to 54 mo nths in pecans and stone fruits, and 36 months in apples , wheat grain , and wheat straw. In addition, a freezer storage stability study was conducted in conjunction with the pepper field trials. A separate control s ample of homogenized peppers was fortified with fenbuconazole, RH 9129, and RH - 9130, each at 1.0 ppm , and stored under the same conditions (≤ - 10oC) as the field trial samples. No 0 - day analysis was conducted prior to placing the samples in frozen storage; therefore, the original fortification levels could not be verified. After 16.6 months of frozen storage, the stored samples were analyzed in triplicate along with a control sample and control samples freshly fortified with each analyte at 1.0 ppm. The a verage recovery (corrected for concurrent recovery) was 89% for fenbuconazole and RH - 9130 and 91% for RH - 9129. These data indicate that fenbuconazole, RH - 9129, and RH - 9130 are stable in frozen peppers for up to 16.6 months. Samples from the pepper field trials were stored at < - 10°C for up to 1 6.4 months prior to analysis. Conclusions : In the pepper storage stability study, no 0 - day analysis was conducted on the fortified samples prior to storage. However, for the purposes of th is pepper tolerance petition, HED accepts the available data to support the pepper field trials. 5.3 Residue Data 5.3.1 Crop Field Trials (860.1500) D 390352, S. Oonnithan, 9/8/2011 Dow AgroSciences has submitted a bridging study on pepper to translate residues from Indar 7 5WSP (EPA Reg. No. 62729 - 421) to Enable 2F (62719 - 416) , thereby obviating the need for aFenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 17 of 25 full field trial data set for the Enable 2F formulation use on peppers . The original submission did not include a petition for a revised tolerance for fenbuconazole r esidues in pepper. The bridging study conducted on bell pepper consisted of side - by - side trials in six locations, in which both formulations were applied to peppers. The submitted residue data (6 samples) for the WP and EC formulations were analyzed usin g the OECD MRL calculator for the purpose of comparing the data sets from the previously reviewed field trials used to establish the existing tolerance and the new bridging data. The results of the comparison are shown below: Table 5.3.1. Fenbuconazole Total Residue 1

Indar WSP 2008 Data Indar WSP

Bridging Study Enable 2F Bridging Study Current or recommended tolerance 0.4 0 0.7 0 1.0 Lowest residue 0.05 0.029 0.044 Highest residue 0.22 0.465 0.668 Mean residue 0.136 0.142 0.189 No. of samples (avg . of 2 replicates ) 18 6 6 1 -- See D390352, S. Oonnithan, 8 Sept 2011. Conclusions : Alt hough the submitted bridging residue data on pepper using the WP (Indar) and SC (Enable 2F) formulations of fenbuconazole are limited, the results summarized above indicate the presence of significantly higher residues of fenbuconazole than found in the earlier field trials . Based on the submitted data, the current 0.40 ppm tolerance does not support the higher residues found on pepper with either the WP formulation or the SC formulation. Therefore, the existing tolerance should be increased to 1.0 ppm to support use of the SC formulation. HED notes that the residue values for bell and non - bell peppers in the o riginal submission were very similar (MRID 47215801) ; therefore, we conclude that the use of only bell peppers in the bridging study is not an issue. Triazole Metabolites Residues o f 1,2,4 - triazole and t riazole acetic acid were non - detectable (<0.003 pp m) in all treated pepper samples. Triazole alanine residue ranged from 0.0187 to 0.158 ppm in treated peppers. Untreated control pepper samples also had triazole alanine residues which ranged from 0.0029 to 0.013 ppm. Table 5.3.2. lists the results from the triazole metabolite analyses and is taken directly for the study report.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 18 of 25 Table 5.3.2. Bell Pepper Field Trial Data for Fenbuconazole (Triazole Metabolites).

Conclusions : There were no significant differences in triazole metabolite residue level resulting from treatment with either formulation. Residues of 1,2,4 - triazole and triazole acetic acid were all non - detectable (<0.003 ppm). Residues of triazole alanine averaged 0.025 ppm, while the maximum observed residue for triazole al anine was 0.158 ppm. These triazole metabolites will be addressed in a separate forthcoming risk assessment. 5.3.2 Field Rotational Crops (860.1900 ) D259204, S. Oonnithan, 7/25/06 An adequate confined rotational crop study is available indicating that the metabolite profile for fenbuconazole i n rotational crops is similar to the metabolism in primary crops. Limited rotational crop field trials and rotational crop tolerances are not required provided that the labels specify a minimum PBI of 35 days following the last application to peppers of ≤0.188 lb ai/A , and a minimum PBI of 210 days following a last application of 0.188 - 1.0 lb ai/A. 5.3.3 Processed Food and Feed (860.152 0) HED does not require residue data for any processed commodities assoc ia ted with peppers . Therefore, data requirements for processed food and feed are not relevant to th ese tolerance petition s.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 19 of 25 5.3.4 Meat, Milk, Poultry and Eggs (860.1480) As t here a re no livestock feedstuffs associated with the proposed /established use s on peppers, d ata requirements pertaining to meat, milk, poultry, and eggs are not relevant to th ese tolerance petition s. 5.3.5 Dietary Burden There are no animal feed commodities associated with use on peppers. Therefore, there is no change in the anticipated dietary burden for livestock commodities. Conclusions : The re is no change in anticipated dietary burden and the current tolerances for livestock commodities are adequate. 5.3.6 Estimated Secondary Residues in Livestock There are no animal feed commodities associated with use on peppers. Conclusions : The current tolerances for livestock commodities are adequate. 5.3.7 . Food Handling (860.1460) There are no proposed u ses that are relevant to this guideline topic . 5.3.8 Water, Fish, and Irrigated Crops (860.1400) There are no proposed uses that are relevant to this guideline topic . 5.4 Food Residue Profile There a re adequate data for risk assessment and tolerance assessment . There were finite r esidues of the parent compound in/ on peppers in the bridging study, and there were very low levels or non - detectable levels of the metabolite RH - 9129. Residue levels for the RH - 9130 metabolite were all below the LOD. Residues of the parent compound tend ed to decline with increasing PHI with an est imated half - life of between 8 to 9 days. 6.0 Tolerance Derivation 

### The bridging study conducted using bell pepper s c onsisted of side - by - side trials in six different location s, in which both formulations were applied in accordance with the registered appli cation rate on peppers . The submitted residue data (6 samples /each an average of two duplicate samples ) for the WP and EC formulations were analyzed using the OECD MRL calculator for the purpose of comparing the data sets from the field trials used to est ablish the tolerance and the new bridging data . The results of these tolerance calculations are summarized in Appendix B.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 20 of 25 Attachment s : A ppendix A . International Residue Limits Table . A ppendix B. OECD MRL Calculation Procedure Inputs/Outputs. Appendix C. Proposed Metabolic Pathway for Fenbuconazole in Crops. Appendix D . Fenbuconazole and Its Metabolites in Plants and Animals .Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 21 of 25 Appendix A . International Residue Limits Table . Fenbuconazole (129011; 10/10/2012) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 40 CFR § 180.480 Plant/Livestock: combined residues of the fungicide fenbuconazole, alpha - [2 - (4 - chlorophenyl) - ethyl] - alpha - phenyl - 3 - (1H 1,2,4 - triazole) - 1 - propanenitrile, and its metabolites RH - 9129, cis - 5 - (4 - chlorophenyl) - dihydro - 3 - phenyl - 3 - (1H 1,2,4 - triazole - 1 - ylmethyl) - 2 - 3 H - furanon e, and RH - 9130, trans - 5 - (4 - chlorophenyl)dihydro - 3 - phenyl - 3 - (1H - 1,2,4 - triazole - 1 - ylmethyl) - 2 - 3 H - furanone, expressed as fenbuconazole α - [2 - (4 - chlorophenyl)ethyl] - α phenyl - 1 H

- 1,2,4 - triazole - 1 - propanenitrile, including the metabolites cis - 5 - (4 - chlorophen yl) - dihydro - 3 - phenyl - 3 - (1 H

- 1,2,4 - triazol - 1 - ylmethyl) - 2 - 3 H

- furanone and trans - 5 - (4 - chlorophenyl) - dihydro - 3 - phenyl - 3 - (1 H - 1,2,4 - triazol - 1 - ylmethyl) - 2 - 3 H

- furanone F enbuconazole. The residue is fat - soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Pepper 1.0 0.6 peppers 2 peppers Chili, dried (draft MRL awaiting ARfD evaluation)

Completed: M. Negussie; 10/12/2012 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those prop osed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quant itation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have no t been finalized by the CCPR and the CAC.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 22 of 25 A ppendix B . OECD MRL Calculation Procedure Inputs/Outputs . Peppers - Different Formulations Crop Peppers – Enable formulation Peppers – Indar formulation Region / Country USA USA GAP 0.188 lbs ai/A / appln. (0.75 lbs ai/A/season) 0.188 lbs ai/A/appln. (0.75 lbs ai/A/season) Total number of data (n) 6 6 Percentage of censored data 0% 0% Number of non - censored data 6 6 Lowest residue 0.059 0.032 Highest residue 0.607 0.411 Median residue 0.124 0.100 Mean 0.189 0.142 Standard deviation (SD) 0.208 0.138 Correction factor for censoring (CF) 1.0 1.0

- Highest residue 0.607 0.411

- Mean + 4 SD 1.019 0.696

- CF x 3 Mean 0.567 0.427 Unrounded MRL 1.019 0.696 Rounded MRL 1 0.7 Residues (mg/kg) 0.607 0.411 0.077 0.062 0.059 0.032 0.141 0.124 0.107 0.075 0.143 0.150Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 23 of 25 Appendix C. Proposed Metabolic Pathway for Fenbuconazole in Crops.Fenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 24 of 25 Appendix D. Fenbuconazole and Its Metabolites in Plants and Animals. Fenbuconazole and Its Metabolites in Plants and Animals. Common name/code Chemical name Chemical structure Fenbuconazole RH - 7592 α - [2 - (4 - chlorophenyl)ethyl] - α - phenyl 1 H - 1,2,4 - triazole - 1 - propanenitrile

Iminolactone Metabolite RH - 6468 5 - (4 - chlorophenyl) - 3 - phenyl - 3 - (1H 1,2,4 - triazol - 1 - ylmethyl)dihydrofuran 2(3H) - imine

Lactone A and B Metabolites RH - 9129 and RH - 9130 trans - or cis - 5 - (4 - chlorophenyl)dihydro - 3 - phenyl - 3 - (1 H1,2,4 - triazol - 1 - ylmethyl) - 2(3 H ) - furanone
Benzylic Alcohol Metabolite RH - 6648 4 - (4 - chlorophenyl) - 4 - hydroxy - 2 - phenyl - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl) butanenitrile

Ketone Metabolite RH - 6467 4 - (4 - chlorophenyl) - 4 - oxo - 2 - phenyl - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl)butanenitrileFenbuconazole Summary of Analytical Chemistry and Residue Data Barcode D 403620

Page 25 of 25 Fenbuconazole and Its Metabolites in Plants and Animals. Common name/code Chemical name Chemical structure 4 - Phenol Metabolite RH - 1311 4 - (4 - chlorophenyl) - 2 - (4 - hydroxyphenyl) - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl)butanenitrile

3 - Hydroxy - 4 - chlorophenyl Metabolite RH - 4911 4 - (4 - chloro - 3 - hydroxyphenyl) - 2 - phenyl - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl) butanenitrile Glucosyl conjugate of RH - 4911 RH - 7905 α - [2 - [4 - chloro - 3 - (D glucopyranosyloxy) phenyl]ethyl] - α phenyl - 1H - 1,2,4 - triazole - 1 - propanenitrile

Cleaved Alcohol Metabolite RH - 7968 4 - (4 - chlorophenyl) - 2 - (hydroxymethyl) - 2 - phenylbutanenitrile Triazole RH - 0118 1H - 1,2,4 - triazole

Triazolealanine TAA RH - 3968 2 - amino - 3 - (1H - 1,2,4 - triazol - 1 - yl) propanoic acid

Triazoleacetic acid TA RH - 3779 RH - 4098 1H - 1,2,4 - triazol - 1 - yl acetic acid